IFN-γ Induced Nitric Oxide Leads to the Inhibition of TH17 Differentiation via iNOS

Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), driven by autoreactive T cells that mediate demyelination, axonal loss, and neuroinflammation. Among the pathogenic T helper subsets, Th17 cells are pivotal in MS progression, producing high levels of proinflammatory cytokines such as IL-17. While Interferon-gamma (IFN-γ) is traditionally seen as proinflammatory, recent findings highlight a paradoxical protective role by inhibiting Th17 differentiation. In this thesis, we explored how IFN-γ, through its regulation of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) production, influences Th1 and Th17 responses in the Experimental Autoimmune Encephalomyelitis (EAE) model and in vitro T cell assays. Our results demonstrate that the absence of IFN-γ signaling exacerbates EAE severity and elevates Th17 cell frequency, underscoring IFN-γ’s protective capacity. In vitro, IFN-γ dose-dependently suppresses Th17 differentiation while promoting Th1 responses. Contrary to expectations, iNOS inhibition did not significantly enhance Th17 cells, though the NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) boosted Th1 cells and modestly reduced Th17 cells. Notably, IFN-γ signaling was necessary for robust iNOS expression during EAE, pointing to a critical IFN-γ–iNOS–NO axis in regulating Th17-driven pathology. These findings underscore the complex role of IFN-γ in modulating Th17 responses and highlight potential therapeutic targets involving NO pathways to mitigate autoimmune inflammation in MS.

Author dc:creator

• Naseem, Yashfa

Contributors dc:contributor

• Forsthuber, Thomas
• Ramos, William
• Guentzel, Neal

• EAE
• IFN-γ
• iNOS
• Nitric Oxide (NO)
• TH17
• Central nervous system
• Multiple Sclerosis
• Autoimmune disease
• T cell assays

Language dc:language

eng

Identifier

9798314895948

OAI identifier oai:identifier

oai:tdl-ir.tdl.org:20.500.12588/7328